The Role of Tcf7l2 in Hepatic Glucose Metabolism in Vivo

Single-nucleotide polymorphisms (SNP) within the transcription factor 7-like 2 (TCF7L2) gene have been consistently associated with an elevated risk for type 2 diabetes (T2DM) in multiple populations throughout the world, but the mechanisms by which TCF7L2 affects the pathways important for the development of T2DM are still poorly understood. Addressing this question is of major importance, primarily because functional investigations into T2DM candidate genes will reveal novel molecular pathways that affect important physiological processes that are highly disturbed in T2DM. In several human studies, carriers of the T-allele for the 'at-risk' SNP (rs7903146) have impaired hepatic glucose production (HGP) and hepatic insulin sensitivity. Preliminary findings from the laboratory of Dr Norton demonstrating that silencing of TCF7L2 markedly up- regulates HGP in vitro, strongly support a role for TCF7L2 in the pathways of HGP. The aim of this proposal is to establish the functional role of the T2DM candidate gene TCF7L2 in HGP in vivo, and to investigate the molecular mechanisms by which TCF7L2 affects the pathways of glucose metabolism in the liver. A combination of integrative physiology and genomics approaches will be used to address the central hypothesis that TCF7L2 is a major regulator of HGP in vivo and that transcriptional control of key metabolic genes by TCF7L2 in the liver is the underlying mechanism of this regulation. The major training component of this proposal is the acquisition, refinement and application of new skills, with focus on two areas: (i) integrated physiology, and (ii) functional genomics and bioinformatics. These thematic areas were selected because at the present time knowledge about these areas is extremely valuable to conduct cutting-edge diabetes research, and these areas are cohesive and highly integrated with the scientific goals of this project. In addition, the scientific objectives of this proposal will be coupled with an intensive career development plan that will include formal coursework in grantsmanship and translational science. The Diabetes Division at the UTHSCSA, chaired by the mentor on this project Dr DeFronzo, is the ideal environment in which to perform this research and to further enhance Dr Norton's expertise in diabetes research. PUBLIC HEALTH RELEVANCE: T2DM is a disease which affects approximately 150 million people worldwide, and those with the disease suffer increased morbidity from micro- and macro-vascular complications. While there is unequivocal evidence that genes play a central role in the development of T2DM, the central question is: how do candidate susceptibility genes contribute to an individual's risk for T2DM at the molecular and physiological level? The proposed studies will describe novel pathways by which TCF7L2 affects a physiological function which is highly disturbed in T2DM. These pathways may unlock new avenues for treatments which, in the future, might help to lessen the impact of a disease which affects 8% of the US population and has reached epidemic proportions. Type 2 diabetes is a disease which affects approximately 150 million people worldwide, and those with the disease suffer increased morbidity from micro- and macro-vascular complications. Elevated blood glucose (hyperglycemia) is the hallmark feature of type 2 diabetes and is thought to be directly responsible for most of the complications associated with the disease. In diabetic patients, increased glucose production from the liver is a key factor in the development of overt hyperglycemia and, as a consequence, the molecular and metabolic pathways responsible for hepatic glucose production are under intensive investigation. We have discovered that a recently identified type 2 diabetes susceptibility gene, TCF7L2, is important in the regulation of the pathways involved in glucose production from the liver. The aim of the current proposal is to test the hypothesis that TCF7L2 is a major regulator of hepatics glucose production in mouse liver and to investigate the molecular and physiological mechanisms responsible for this effect. We plan to use sophisticated in vivo physiological studies, combined with highly novel molecular and genomics approaches to examine this central hypothesis